10-hydroxyalkaloids and method of making



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Henri}; oport and-Satoru-Masamune, Berkeley, Calif as ign {o The.Regents of k'tll'e" l University of} Cali st ia'Bsrk li NmDraWia s Ap lca ion J nuar 131. 9.5 1. """'SQfiELNSfigQk.'

9 Claims. or. 260-285) inxe on melaton n. end nee e al s. o t 9!? s 'sQhXQ PQYWQ PhiH toathe pro.- vi 0 mrthq fimkins.smhcoaunound;and tothe-provision of certain intermediate 10-hydroxyalkaloids resulting fromsuchmell fim Although morphine is one of the most effective analgesicsknown, it is also toxic and overdoses of it can prove to be fatal.Therefore, for many years researchers have attempted to find less toxicderivatives of this drug, or substitutes therefor. We have found thatl0-hydroxymorphine has a much higher safety ratio-the ratio of toxicdose to analgesic dosethan morphine.

Since cold chromic acid oxidation has been applied to codeine and anumber of its derivatives, it was thought that the same generalprocedure could be readily applied to several additional alkaloids ofthe morphine group for the purpose of hydroxylating them at the10-position. (See H. Rapoport and G. W. Stevenson, Journal of AmericanChemical Society, 76, 1796 (1954), and H. Rapoport and Satoru Masamune,ibid, 77, 6359, (1955).) While this reasoning proved to be correct withrespect to neopine and A' desoxycodeine, it proved to be entirelyincorrect with respect to morphine, the most important compound of thegroup.

Before the oxidation procedure in question could be applied to morphine,we found it was necessary to find asuitable protecting group for thephenolic hydroxyl in order to prevent oxidation of the aromatic ring.Furthermore, such a group, in addition to being stable to acid andoxidation, had to be capable of being removable under mild conditions,since the 'hydroxylated molecule would then contain a secondary benzilicalcohol, a secondary allylic alcohol, and an alicyclic double bond.

General oxidation procedure In carrying out the objects of ourinvention, all oxidations followed the general procedure set forth inthe two literary references above referred to, but O -allylmorphine wasused as a starting material rather than morphine, for morphine, as abovestated, is not suitable for this purpose.

To this end, a solution of chromic acid in 10 N sulfuric acid was addedto a well-stirred solution of O -a1lylmorphine in 1 N sulfuric acidmaintained at 35 C. For 12.7 g. of O -allylmorphine, 2000 ml. of 1 Nsulfuric acid; 2.64 g. of chromic acid, and 132 m1. of 10 N sulfuricacid were used, and the addition was made over a six to eight-hourperiod from a capillary-tipped dropping funnel extending below thesurface of the alkaloid solution. One hour after completion of theaddition, sodium sulfite was added to destroy any excess oxidant. Thesolution was adjusted to pH 4-5 with sodium carbonate, and then it wasmade strongly alkaline with sodium hydroxide prior to extraction with asuitable solvent such as chloroform.

Preparation of 0 -allyl-1O-hydroxymorphine v The oxidation of the 12.7g. of O -allylmorphine and the extraction thereof with chloroform asabove set forth United States Patent 0 2; left 8.2 g. of residue. This m'a1,wa s.. app l ied to an alumina column (6.5 3.3- .0. mJuubenzenechloroform (7:3) and by gradualy '1 i ent to lzl, 28 ,s "rt1{mater'i wa's'rcovered. i 1 .0 1n pound) whicl 'l was fro .c. 351acetate and s'ublinied: t I l,3;;g. l0'percclnt); Man 113755.439; v (Q851 m r. Mas ns; as

A solution carom-mg. 2 i05 mmoles) of O allyl-l0- hydroxyrnorphine incof liquid; ammonia was trat'edlwith-Z 230mg.- (:1-0 mmole's) of sodiumportions with stirring. The vigorous gas evolution soon subsided andaprnianeritfblue fl color developed within "about; 10 minutes, after.whicli 0;7 -ml.= of-fmethanolwas addedand the .fiow..colorless solutionwas-evaporated under -a nitroge'ntstreamand t-heirinwacuo; Solution ofthe residue water (114811 1512) was prepared, 'theadjustment of the pHof the solution of 8.3 with an acid, such as hydrochloric acid, andcooling gave 550 mg. of a yellow, crystalline precipitate which wasextracted with acetone in a Soxhlet extractor for two days. The solid inthe boiling flask plus the additional material obtained on concentratingthe acetone was dissolved in 300 ml. of 50 percent aqueous ethanol andthis solution was treated with 200 mg. of decolorizing carbon, filtered,and concentrated to dryness.

Preparation of triacetyl-10-hydroxymorphine The resulting 490 mg. (79percent yield) of lO-hydroxymorphine was purified further through thetriacetyl derivative. Heating a solution of l g. of 10-hydroxymorphinein 35 ml. of acetic anhydride and 5 ml. of pyridine for seven hours atC. and evaporating the solution to dryness in vacuo left a residue whichwas chromatographed on alumina (acid washed, 3.5 x 6 cm.). Thechromatogram was developed with benzene and the elution was completedwith benzene-chloroform (8:2 and 1:1). Crystallization from ethylacetate gave 1.16 g. (82 percent yield) of triacetyl-10-hydroxymorphine,a new compound; M. P. 186-187 C., [M -86.8 (C. 9.93, ethanol).

Analysis.-Calcd. for C23H25O'1N: C, 64.6; H, 5.9. Found: C, 64.5; H,6.1.

Preparation of purified IO-hydroxymorphine To obtain 10-hydroxymorphine, a solution of the triacetyl derivative in 0.5 N sodiumhydroxide in 50 percent aqueous ethanol was heated under refluxovernight in a nitrogen atmosphere. The solution was concentrated invacuo to one-sixth its volume, the pH was adjusted to 8.3, and theprecipitated white, crystalline 10- hydroxymorphine was filtered fromthe cooled solution in 93 percent yield. It was washed with water,ethanol, and ethyl acetate and dried at 100 C. in vacuo; M. P. 325 C.with dec. after sintering at 230-240 C.; [od -94.5 (C. 0.69, 2 N aceticacid).

Analysis.-Calcd. for C17H19O4N: C, 67.8; H, 6.4. Found: C, 68.0; H, 6.7.

It should here be noted that the intermediate compounds O-allyl-l0-hydroxymorphine and triacetyl-IO-hydroxymorphine are newcompounds, as well as the 10- hydroxymorphine, and that the utility ofthe former resides, among other things, in the fact that they serve asstarting materials from which the 10-hydroxymorphine can be produced inaccordance with our method. The latter compound is, of course, highlydesirable in that it has a much higher safety ratio than morphine.

phine comprising subjecting O -allylmorphine to cold chromic acidoxidation, wherein a solution of. chromic acid in 10 N sulfuric acid isadded to a well-stirred solution of O -allylmorphine in l N sulfuricacid maintained at 3-5 C. in the following proportions: for 10 m1. of

O -allylmorphine, 500 ml. of l N sulfuric acid, 0.66 g.

of chromic acid, and 33 ml. of 10 N sulfuric acid; wherein after thecompletion of said addition, sodium sulfite is added to destroy anyexcess oxidant, the pH of the solu -tion is adjusted to pH 45 and thenmade strongly alkaline, and wherein the solution is extracted with asuitable solvent such as chloroform.

6. The method of preparing O -allyl-lo-hydroxymorphine comprisingsubjecting O -allylmorphine to cold chromic acid oxidation in accordancewith claim 5; applying the resulting residue to an alumina column usingbenzene-chloroform (7:3); and gradually changing the solvent to 1:1.

7. The method of preparing crude l0-hydroxymorphine comprising treatinga solution of O -allyl-10-hydroxymorphine in liquid ammonia with sodiumwith stirring and permitting the resulting evolution of gases tosubside; adding methanol to the solution and drying it to produce aresidue; preparing an aqueous solution of said residue and adjusting itspH to 8.3; cooling said solution to produce a crystalline precipitate ofcrude IO-hydroxymorphine.

8. The method of producing triacetyl-10-hydr0xymorphine comprisingheating a solution of crude l0j-hydroxymorphine in acetic anhydride andpyridine and evaporating the solution to dryness to produce a residue;chromatographing said residue on alumina and developing the chromatogramwith benzene and completing the elution with benzene-chloroform. it t.

9. The method of preparing lO-hydroxymorphine comprising preparing asolution of triacetyl-10-hydroxymorphine in sodium hydroxide in aqueousethanol and heating said solution under reflux in an inert atmosphere;concentrating the solution and adjusting it pH to 8.3,

No references cited.

1. A 10-HYDROXYLKALOID SELECTED FROM THE GROUP CONSISTING OF10-HYDROXYMRPHINE, O3-ALLYL-10-HYDROXYMORPHINE ANDTRIACETYL-10-HYDROXYMORPHINE.